The long term objective of these studies is to better understand mechanisms that regulate tone of cerebral blood vessels under physiological and pathophysiological conditions. Both endothelium and neurons produce nitric oxide (NO) or a related NO- containing compound. Excitatory amino acids produce marked increases in cyclic GMP in brain tissue which appear to be mediated by NO produced by neurons. I have obtained preliminary evidence that the glutamate analogue N-methyl-D-aspartate (NMDA) produces dilatation of pial arterioles in vivo that is dependent on neuronal activation and generation of NO. Thus, a previously undescribed glutamate-NO system may exist which mediates local vasodilatation during increased neuronal activity in brain. The first aim of these studies is to examine the hypothesis that dilatation of pial arterioles in response to excitatory amino acids in vivo is mediated by NO. Studies of cerebral arteries in vitro will be performed to exclude possible direct effects of excitatory amino acids on endothelium, smooth muscle, and vasodilator innervation. I also propose to determine whether formation of NO contributes to dilatation of cerebral microvessels during seizures, which produce endogenous accumulation of excitatory amino acids. Functional responses to activation of glutamate and NHDA receptors and the ability of brain to generate cyclic GMP in response to NMDA, decrease with aging. The second aim of these studies is to examine the hypothesis that dilatation of cerebral arterioles in response to activation of receptors for excitatory amino acids on neurons is impaired with aging. I also propose to determine whether treatment with L-arginine, the precursor of NO, enhances responses of cerebral arterioles in aged rats to NMDA. The proposed studies should provide a greater understanding of the influence of NO in regulation of the cerebral circulation under normal conditions and during aging.